1) Field of the Invention
The present invention relates to a linear biodevice, a membrane-like biodevice and a bioreactor using them, and more specifically to a linear or membrane-like biodevices and a bioreactor in which adhesive cells are anchored at high density.
The biodevices and the bioreactor of the present invention are useful for production, conversion, or separation of a useful substance by taking advantage of adhesive cells.
2) Description of the Related Art
Conventionally, as to a method of making cells in a membrane-like form, there is a method in which cells anchored to a flat bottom surface of a container that has been treated with a temperature sensitive polymer are detached by taking advantage of extension of the temperature sensitive polymer, and the method is used for regeneration of cornea and the like.
Further, various properties and forms of materials have been studied as a carrier to which adhesive cells are anchored. In a bioreactor, adhesive cells are anchored to a flat surface arranged in a flow path or a fiber aggregate.
In recent years, a permeable cell culture carrier, and a culture method and a culture device that use this carrier have been proposed (for example, Japanese Patent Application Laid-Open Publication No. 1995-298876), and it has been disclosed that when any one of a plurality of natural or synthetic threads and textile or both are used as a carrier, permeability can be secured, animal cells proliferate three-dimensionally, and tissues can be self-formed with a high survival rate.
Further, with respect to a culture substrate for adhesive animal cells, it has been disclosed (for example, Japanese Patent Application Laid-Open Publication No. 1996-33743, Japanese Patent Application Laid-Open Publication No. 1996-33474, and Japanese Patent Application Laid-Open Publication No. 1996-33475) that when the culture substrate that has a basic functional group, an acidic functional group, or a neutral functional group on a fiber aggregate constituted of fibers of 20 to 60-micrometer fiber diameters and formed in a manner that the fibers are intertwined with one another with fiber surface area of 10 to 30 m2/m3 and porosity of 90% is used, the cells adhere to the fiber surface, proliferate, and extend, and further exhibit multilayered growth, and therefore, it is possible to immobilize the cells at high density and form a porous structure.
However, such a conventional technology has the following problems.
That is, since there is no supporter in a cell sheet prepared by detaching cells that have been immobilized to a flat bottom surface of a culture container, a strength of the sheet alone is not sufficient, which gives rise to a problem that handling becomes complex.
Further, when cells are anchored to a flat bottom surface of a culture container, the cells extend to adhere to it. Therefore, not only do the cells occupy an area that is several times of the cell diameter in suspension but also proliferation of the cells stops in a confluent state, which gives rise to a problem that the cells cannot be immobilized at high density.
When a porous material is used as a carrier, it is difficult for cells to be formed in a membrane-like shape, and it is impossible for the cells to be immobilized at high density. Further, it is also impossible to swiftly supply oxygen and nutrients essential for animal cells to the inside of the carrier, which gives rise to another problem that only the vicinity of the surface of the carrier functions.
On the other hand, when a fiber aggregate is used as a carrier, it is so porous that convection takes place owing to good permeability, which does not allow cells to be immobilized at high density and the carrier to which the cells are anchored to play a role of a partition, and therefore, it is impossible to allow the cells to make contact with two kinds of fluids without being mixed with each other.